Allogeneic bone marrow transplantation can produce sustained remissions and cure in some patients with hematologic malignancy. However, successful transplantation is limited by the availability of suitable donors, the development of potentially fatal transplant-related complications, and disease recurrence. In this Project, we plan to explore a series of immunomodulatory approaches aimed at reducing the complication rate and improving the efficacy of allogeneic BMT. We have previously shown that T cell depletion with anti-CD6 monoclonal antibody and complement can reduce the incidence of GVHD, and with it, transplant related mortality. We now intend to evaluate this approach in recipients of marrow from unrelated donors. Unrelated marrow transplantation is currently associated with significant morbidity and mortality due in part to the high incidence of GVHD and opportunistic infection; attempts to improve the safety of unrelated transplantation are needed if this is to be more broadly applied in the treatment of malignancy. We have already demonstrated that low dose IL-2 is a potent stimulator of NK cells in vivo and that IL-2 treatment following CD6 depleted BMT may reduce the risk of disease relapse. During the upcoming funding period, we hope to explore new ways to modify IL-2 administration post-BMT to facilitate delivery and to increase the cytolytic potential of NK cells. We will evaluate the interaction of IL-2 with newly described cytokines such as IL-12 and IL- 15. It is hoped that such studies will lay the framework for the development of new clinical initiatives designed to further assess the contributions NK cells make to anti-tumor immunity. These trials will also provide an opportunity to determine if cytokine administration can contribute to restoration of T cell functional immune competence in the early post-transplant period. The final aim of this project explores the role of donor hematopoietic chimerism and its relationship to disease relapse post-BMT. The aims of this project are closely interrelated with those of the other projects in this program and together we hope to make important advances towards improving the safety and effectiveness of allogeneic BMT.